Neurosci Bull︱Qian Lingjia's research group reveals that homocysteine ​​affects cognitive function by regulating DNA methylation during chronic stress

‍‍‍‍‍‍‍‍‍Stress refers to the non-specific response of the body to the whole body when it is stimulated by various internal and external environmental factors [1]
.

With the accelerated pace of work in recent years, stress from various aspects has gradually become a potential killer affecting human health
.

Current research believes that long-term high-intensity stress has a clear damage effect on the body [2].
The brain, as an advanced organ responsible for animal recognition and response to stress, is also highly susceptible to stress, which is mainly reflected in cognitive impairment.
and so on
.

As an important brain region responsible for learning, memory and emotion, the hippocampus is highly susceptible to stress[3]
.

A large number of studies have found that chronic stress has negative effects on the hippocampus in many aspects, such as damage to the cell structure, resulting in abnormal function [4]
.

However, the molecular mechanism of stress-induced cognitive impairment has not been fully revealed, compared to the earlier and more fully concluded stress-induced damage to the hippocampal structure
.

Homocysteine ​​(Hcy) is a small molecular amino acid converted from methionine in animals.
Epidemiological studies have found that the level of Hcy is closely related to the occurrence of cognitive impairment in the population [ 5], and the Hcy levels in the plasma and brain of the animals were significantly increased under stress conditions
.

However, whether and how Hcy is involved in stress-induced cognitive impairment remains unclear
.

 On April 18, 2022, Qian Lingjia's research group from the Academy of Military Medical Sciences published a paper entitled "Homocysteine-Induced Disturbances in DNA Methylation Contribute to Development of Stress-Associated Cognitive Decline in Neuroscience Bulletin".
Rats" research paper, proposing the mediating role of Hcy in the process of chronic stress-induced cognitive impairment
.

Dr.
Wang Shida and Assistant Researcher Wang Xue are the co-first authors of the paper, and Associate Researcher Xie Fang and Researcher Qian Lingjia are the corresponding authors of the paper
.

The authors found that chronic stress induces cognitive impairment, and that elevated Hcy is an important cause of cognitive impairment, while the level of brain-derived neurotrophic factor (BDNF) in the hippocampus decreases; further mechanisms Studies have found that elevated Hcy inhibits the transcription and expression of BDNF in the hippocampus by affecting the methylation modification of BDNF promoter DNA 5mC, which ultimately leads to cognitive impairment
.

This article enriches the molecular mechanism of stress-induced cognitive impairment at the animal level and provides a potential target for controlling stress
.

In order to study the changes of cognitive function and the changes of Hcy during chronic stress, the authors first used the 8-week Chronic Unpredictable Mild Stress Model (CUMS) to simulate the effects of chronic stress on animals, and tested them at different time points.
Behavioral changes and plasma Hcy levels
.

The results showed that the cognitive function of the animals decreased with increasing stress time course, and the decrease was stable and significant after the 6th week (Fig.
1 AE)
.

At the same time, the plasma Hcy level increased with the increase of stress time course (Fig.
1F), and various cognitive functions were negatively correlated with Hcy (Fig.
1GJ)
.

The above results suggest that there is a significant correlation between Hcy and cognitive function
.

In order to further clarify whether Hcy is the cause of cognitive impairment, the authors supplemented B vitamins on the basis of stress and administered a high-methionine diet to achieve up-regulation and down-regulation of Hcy, respectively (Fig.
1K)
.

The results showed that supplementation with B vitamins to downregulate Hcy improved cognitive impairment due to stress, while a high-methionine diet mimicked the effects of stress on cognitive function (Fig.
1 LO)
.

The above results suggest that Hcy is one of the causes of stress-induced cognitive impairment
.

Figure 1 Hcy is one of the causes of stress-induced unknowing disorder (Source: Wang SD, et al.
, Neurosci Bull, 2022) Further research, the authors focused on the changes in the transcription and expression of BDNF in the hippocampus during stress.
The results showed that with the increase of stress time course, BDNF gene transcription and protein expression levels in the hippocampus decreased (Fig.
2A, B), and were negatively correlated with Hcy levels (Fig.
2C)
.

In addition, the level of BDNF in the hippocampus was increased after down-regulation of Hcy, and the density of dendritic spines in the hippocampus was increased compared with the stress basis, while the level of BDNF was decreased and the density of dendritic spines was decreased after up-regulation of Hcy (Fig.
2DF)
.

It is suggested that Hcy has a potential negative regulatory effect on BDNF during stress
.

In order to clarify whether BDNF changes are involved in cognitive dysfunction during stress, the authors overexpressed BDNF in the hippocampus on the basis of stress intervention (Fig.
2 G, I).
The results showed that overexpression of BDNF could not affect stress.
On the basis of higher Hcy levels during the process (Fig.
2H), various cognitive levels of rats (Fig.
2 JN) were improved, suggesting that BDNF is a downstream target of Hcy in the process of stress-induced cognitive impairment
.

Figure 2 The down-regulation of BDNF is closely related to the occurrence of cognitive impairment during stress (Source: Wang SD, et al.
, Neurosci Bull, 2022) Given that Hcy is involved in the body's methylation metabolism, the authors focused on the subsequent study The effect of Hcy on DNA 5mC methylation during stress was investigated
.

The results showed that Hcy led to a decrease in the methylation potential of the hippocampus during stress (Fig.
3A), and the degree of methylation modification of 5mC in genomic DNA was decreased (Fig.
3B)
.

The authors also focused on the alteration of methyl metabolizing enzymes, and the results showed that Hcy led to increased expression levels of DNMT1 and 3b, while the remaining DNA 5mC methyl metabolizing enzymes were not significantly altered (Fig.
3C)
.

In order to further study the effect of Hcy on the methylation of the BDNF gene promoter, the authors used methyl-specific PCR experiments and Sequenom sequencing technology to detect it, and the results showed that Hcy caused BDNF promoter DNA 5mC methylation during stress.
The level of methylation increased, and the degree and trend of methylation changes at different "CG" sites were different (Figure 3D, E), suggesting that the methylation changes of a certain sequence of the promoter reflect the methylation of several sites on the sequence.
Changed composite state
.

Figure 3 Hcy regulates the methylation of BDNF promoter in hippocampus (Source: Wang SD, et al.
, Neurosci Bull, 2022) In order to finally confirm whether changes in BDNF promoter methylation directly affect its transcription and expression levels, The authors achieved the regulation of hippocampal methylation by overexpressing the active demethylase-TET1 on the basis of stressed animals, and focused on the changes of BDNF and its impact on cognitive function
.

The results showed that overexpression of TET1 effectively reduced the methylation level of BDNF promoter 5mC in the hippocampus of stressed animals (Fig.
4F), while the level of BDNF was significantly increased, the density of dendritic spines in hippocampal neurons increased (Fig.
4 AE), cognitive function recovered (Fig.
4 GJ)
.

 The above results suggest that the elevated methylation of BDNF gene promoter may be related to its transcription and expression inhibition, but the specific mechanism still needs further study
.

Figure 4 Overexpression of TET1 downregulates BDNF promoter methylation and improves cognitive function (Source: Wang SD, et al.
, Neurosci Bull, 2022) Conclusions and discussions, inspiration and prospects At the level of in vivo experiments, it was found that elevated homocysteine ​​(Hcy) is one of the important causes of stress-induced cognitive impairment, and further through the up-regulation of the brain-derived nerve growth factor (BDNF) gene promoter in the hippocampus The level of 5mC methylation modification of DNA in the region thus hinders the transcription of the gene
.

This result enriches the mechanism of chronic stress on cognitive impairment from an epigenetic point of view.
At the same time, the intervention of Hcy by complex B vitamins and the intervention of methylation by TET1 proposed in this study are the main factors of stress-induced cognitive impairment, respectively.
Prevention and intervention therapy provide a potential target basis
.

But at the same time, although the authors used TET1 to achieve the regulation of BDNF promoter methylation, as a non-specific intervention, TET1 may also have a regulatory effect on the methylation modification of other genes in this process, so follow-up studies Specific interventions should be selected first for research
.

In addition, the specific mechanism of BDNF promoter 5mC methylation hindering its gene transcription and protein expression needs further study
.

Link to the original text: https://doi.
org/10.
1007/s12264-022-00852-7 First authors Wang Shida (first from left), Wang Xue (second from left); corresponding authors Xie Fang (second from right) and Qian Lingjia (right 1) (Photo provided by: Qian Lingjia Laboratory) Fund support: National Natural Science Foundation of China (31771290, 81702454), Beijing Natural Science Foundation (5222033), Basic Research Program of National Science and Industry Administration (JCKY2019548B001)
.

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18~4.
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Plate making︱Wang Sizhen end of this article‍‍‍‍‍‍‍‍‍‍